Resolution of 7-carboethoxy-3-acetylthioheptanoic acid



United States Patent RESOLUTION OF 7-CARBOETHOXY-3-ACETYL- THIOHEPTANOIC ACID Edward Walton, Scotch Plains, and Arthur F. Wagner,

Princeton, N. J., assignors to Merck & Co., Inc., Rahway, N. 1., a corporation of New Jersey No Drawing. Application July 22, 1954, Serial No. 445,166

3 Claims. (Cl. 260-455) This invention relates to the resolution of chemical compounds into optically active forms or and enanu'omorphs. More particularly, this invention is concerned with the resolution of a heptanoic acid derivative into and enantiomorphs thereof which are useful in the synthesis of optically active forms of a-lipoic acid.

a-Lipoic acid or 5-[3-(l,Z-dithiacyclopentyl)]pentanoic acid is a valuable growth stimulating crystallinesub stance which was obtained from liver and later reported to have the structural formula CHzCHKIJHKCHzhCOOH as is disclosed in the lrArn. Chem. Sec. 74, 3455 (1952). a-Lipoic acid has an asymmetric center and accordingly may exist in optically active forms. In this regard, it has been found that (+)-a-lipoic acid is the natural form of this compound and accordingly the preferred form for usewhere OL-llpOlC acid activity is indicated. Of the various chemical synthetic methods of preparing a-lipoic acid disclosed in the prior art there is apparently no teaching of a method for the preparation of the and enantiomorphic forms of a-lipoic acid.

It is an object. of' this invention therefore to provide novel processes of producing ()-u-lipoic acid and a-lipoic acid. Another objectis to provide novel optically active compounds and processes of preparing the same" which are useful. in synthesizing the optically active forms of a-lipoic acid. Other objects will be apparent from the following description of this invention.

It has now been discovered according to the present invention that mixtures of the and euantiomorphs of 7-carboethoxy-3-acetylthioheptanoic acid such as a racemate thereof may be resolved into and optical isomers. As a result of this discovery, (+)-a-lipoic acid and ()-a-lipoic acid may be conveniently produced according to the processes disclosed in United States patent application Serial No. 445,165, filed July 22, 1954, by utilizing the and optical forms of 7-carboethoxy-3-acetylthioheptanoic acid in place of the racemate in such processes.

The desired resolution of racemic 7-carboethoxy-3- acetylthioheptanoic acid or other mixtures of the and enantiomorphs thereof is achieved according to the present invention by reacting the mixture with l-ephedrine to produce a mixture of (+)-7-carboethoxy- 3-acetylthioheptanoic acid l-ephedrine salt and ()-7- carboethoxy-3-acetylthioheptanoic acid l-ephedrine salt; separating said mixture into the individual and l-ephedrine salts by means of fractional crystallization; and converting said separated l-ephedrine salts to (+)-7- carboethoxy-3-acetylthioheptanoic acid and ()-7-carbo- -ethoxy-3-acety1thioheptanoic acid.

The mixture of (+)-7-carboethoxy-S-acetylthioheptanoic acid l-ephedrine salt and ()-7-carboethoxy-3- acetylthioheptanoic acid l-ephedrine salt is conveniently ture of solvents, but preferably with ethyl ether.

ICE

prepared by intimately contacting7-carboethoxy-3-acetylthioheptanoic acid and l-ephedrine, preferably in equir molar quantities, in a suitable inert liquid reaction medi um. Solvents such as ether, dioxane, lower alcohols, benzene and toluene and aqueous mixtures thereof are suitable reaction media for this purpose. The reaction proceeds at room temperature and is quickly completed. The mixture of and l-ephedrine salts-is conveniently recovered if desired from the reaction mixture by conventional methods-such as filtration or by evaporation todryness.

Separation of the (+)-7-carboethoxy-3-acetylthioheptanoic acid l-ephedrine salt from the ()-7-carboethoxy- 3-acetylthioheptanoic acid l-ephedrine salt by fractional crystallization is conveniently accomplished by intimately contacting said mixture with a suitable solvent or mix- Contact. between the ether and mixture of and l-ephedrine salts may be brought about either by adding said mixture to the ether. or by forming the mixture insitu by efi'ecting the reaction of 7-carboethoxy-3-acetylthioheptanoic acid with l-ephedrine in the presence of ether. As a result of contacting the mixture of and l-ephedrine salts with ether there is obtained at ordinary temperatures, such as room-temperature, a precipitate of (-)-7-carboethoxy-3-acetylthioheptanoic acid l.-ephedrine salt and an ether solution of (+)-7-carboethoxy-3-acetylthioheptanoic acid l-ephedrine salt. By filtratioin or decantation of the ether solution the ()-7- carhoethoxy-3-acetylthioheptanoic acid l-ephedrine salt is. recovered directelyin crystalline form. It may be recrystallized, if desired, from a suitable solvent such as methanol. By evaporating the resulting ether solution tov dryness the (+)-7-carboethoxy-3-acetylthioheptanoicacid l-ephedrine salt is recovered in a noncrystalline form.

The and l-ephedrine salts produced. and isolated as described. above maybe converted tothefree acids ().-7carboethoxy-3-acetylthioheptanoic acidand (+)-7-carboethoxy-3-acetylthioheptanoic acid by treating the corresponding l -ephedrine salts with asuitable acid, and preferably a nonoxidizing mineral acid such as sulfuric acid, hydrobromic acid, hydrochloric acid. and phosphoric acid. This conversion is convenientlyachieved by contacting the l-ephedrine salt and the acid in a liquid reaction medium, preferably in aqueous ororganic solvents such as lower alcohols, benzene, chloroform and mixtures thereof. Although an equivalent amount of acid is sufficient to effect the conversion it is ordinarily desired to employ an excess of acid. Recovery of the desired and isomers from the reaction mixture is conveniently effected by conventional methods such as separating the organic phase when present and evaporating to dryness or by extracting the reaction mixture with a water immiscible solvent and subsequently evaporating the organic extract to dryness. The ()-7- carboethoxy-S-acetylthioheptanoic acid is thus obtained in pure form whereas to obtain (+)-7-carboethoxy-3- acetylthioheptanoic acid in a purified form it is treated further according to the novel methods described immediately hereinafter.

iurification of -7-carboethoxy-S-acetylthioheptanoic acid may be effected by the discovery that said compound reacts with benzhydrylamine in suitable organic solvents and mixtures thereof, including aqueous mixtures, and preferably isopropyl ether, to form a crystalline benzhydrylamine salt of (+)-7-carboethoxy-3-acetylthioheptanoic acid which separates from the reaction mixture. This salt may be recovered by filtration. By acidifying a solution of said salt employing the acids and conditions previously described above there is produced pure 7-carboethoxy-3-acetylthioheptanoic acid.

p The following examples are added to furtherillustrate the invention but it is to be understood that the invention is not to be limited thereby.

EXAMPLE 1' ()-7-cai'b0eth0xy-3-acetylthi0heptan0ic acid and the lephedrz'ne salt thereof A solution of 5 g. of racemic-7-carboethoxy-3-acetylthioheptanoic acid in 50 ml. of ether was mixed with a solution of 3 g. of l-ephedrine in 50 ml. of ether. After the reaction mixture was kept at room temperature for a short time crystalline ()-7-carboethoXy-3-acetylthioheptanoic acid l-ephedrine salt precipitated; M. P. 125 128 C. The product was recrystallized twice from methanol; M. P. 129131 C.

A 2.25 g. portion of-(-)-7-carboethoxy-3-acetylthioheptanoic acid l-ephedrine salt was suspended in 50 ml. of water and 40 ml. of ether. The mixture was acidified with dilute hydrochloric acid and the ether layer was separated. The aqueous phase was extracted with a second 40 ml. portion of ether. The combined ether layers were dried and concentrated under reduced pressure to yield )-7-carboethoxy-3-acetylthioheptanoic acid: n 1.484 {(11 -6.8 (c., 8.5 in methanol).

EXAMPLE 2 (+)-7-carboeth0xy-3-acetylthi0heptan0ic acid and the I ephedrine salt thereof A solution of 153 g. of racemic-7-carboethoxy-3-acetyl thioheptanoic acid inl500 ml. of ether was treated With a solution of 91.5 g. of l-ephedrine in 1500 ml. of ether. The mixture was kept at C. overnight and the precipitated crystalline -7-carhoethoXy-El-acetylthioheptanoic acid l-ephedrine salt removed; M. P. 123-127 C. The filtrate containing (+)-7-carboethoxy-3-acetylthioheptanoic acid l-ephedrine salt was treated with 500 ml. of water and acidified with hydrochloric acid. The ether layer was separated and the aqueous layer extracted with another portion of ether. The combined ether extracts were dried and concentrated under reduced pressure to yield 87 g. of (+)-7-carboethoxy-3-acetylthioheptanoic acid.

About 35 g. of the (+)-7-carboethoxy-3-acetylthioheptanoic acid dissolved in 200 ml. of isopropyl ether was treated with a solution of benzhydrylamine (obtained from 32 g. of benzhydrylamine hydrochloride) in 200 ml. of isopropyl ether. A crystalline benzhydry larnine salt of (+)-7-carboethoXy-3-acetylthioheptanoic acid was pre- I cipitated. It Was recrystallized twice fromisopropyl ether;

M. P. 92-96 C.; [04 +1. 3 (c., 8.06 in methanol).

A 14.0 g. portion of (+)-7-carboethoxy-3-acetylthioheptanoic acid benzhydrylamine salt was dissolved in ml. of chloroform and 100 ml. of Water was added. The mixture was acidified with hydrochloric acid and the chloroform layer separated. 'The chloroform layer was washed with water, dilute hydrochloric acid and twice more with Water. The chloroform layer was dried and concentrated under reduced pressure to yield pure (+)-7- carboethoxy-3-acetylthioheptanoic acid; [och- ;{-6.8 (c., 8.65 in methanol).

Various changes and modifications of the invention can be made and, to the extent that such variations incorporate the spirit of this invention, they are intended to be included within the scope of the appended claims.

What is claimed is:

l. A process which comprises reacting (+)-7-carboethoXy-3acetylthioheptanoic acid with benzhydrylamine in solution in an inert liquid reaction medium in which the resulting benzhydrylamine salt of (+)-7-carboethoxy- 3-acetylthioheptanoic acid is only partially soluble, recovering the crystalline precipitate, treating said crystalline benzhydrylamine salt of (+)-7-carboethoXy-3-acetylthioheptanoic acid with a non-oxidizing mineral acid and recoverin purified -7-carboethoxy-3 -acety1thioheptanoic acid.

2. A process which comprises reacting (+)-7-carboethoXy-3-acetylthioheptanoic acid with benzhydrylamine in isopropyl ether, recovering the crystalline benzhydrylamine salt of (+)-7-carboethoxy-3-acetylthioheptanoic acid which forms, treating said salt in a liquid reaction medium with a non-oxidizing mineral acid and recovering purified -7-ca1'boethoXy-3 -acetylthioheptanoic acid.

3. A benzhydrylamine salt of (+)-7-carboethoxy-3- acetylthioheptanoic acid.

References Cited in the file of this patent UNITED STATES PATENTS Brown et al.: 2123- 25.

Richter: Textbook of'Org. Chem.', 3rd edit, 1952, page 338.

Jour. of the Chem. Soc. (1951), pages 

2. A PROCESS WHICH COMPRISES REACTING (+)-7-CARBOETHOXY-3-ACETYLTHIOHEPTANOIC ACID WITH BENZHYDRYLAMINE IN ISOPROPYL ETHER, RECOVERING THE CRYSTALLINE BENZHYDRYLAMINE SALT OF (+)-7-CARBOETHOXY-3-ACETYLTHIOHEPTANOIC ACID WHICH FORMS, TREATING SAID SALT IN A LIQUID REACTION MEDIUM WITH A NON-OXIDIZING MINERAL ACID AND RECOVERING PURIFIED (+)-7-CARBOETHOXY-3-ACETYLTHIOHEPTANOIC ACID. 